Crowning a quest into a very well-guarded secret: Structure of the
kinetochore corona finally revealed
Date:
April 8, 2022
Source:
Max Planck Institute of Molecular Physiology
Summary:
During cell division in a mother cell, the 23 chromosomes that carry
the human genome must be first copied and later delivered to two
newly forming daughter cells. At least in healthy cells, the result
is astonishingly flawless, and no chromosome is ever lost. Not so
in malignant cells, where rampant chromosome segregation errors
generate a continuous flux of new genetic variants that support
metastatic growth and resistance to chemotherapy. A multilayered
protein structure called the kinetochore executes the chromosome
delivery program.
FULL STORY ==========================================================================
Cell division builds our bodies, supplying all cells in our tissues and
organs, from the skin to the intestine, from the blood to the brain. It
not only allows these organs to grow, but also to regenerate with fresh
cells when required.
Cell division starts with the replication of chromosomes, the carriers
of the three billion nucleotides of the human genome.The replicated
chromosomes are then distributed to the daughter cells in a process named mitosis. During mitosis, a network of thread-like structures named the
mitotic spindle initially captures the chromosomes. After positioning them
in a highly choreographed process, the spindle separates the chromosomes
in opposite direction, so that when two cells form out of one, each
inherits an exact copy of the genome. Even the smallest errors in this
process will have dire physiological consequences.
==========================================================================
A multilayered challenge The kinetochore is the point of contact of
chromosomes with the spindle, and is therefore crucially involved in
the process of chromosome alignment and partition. It is a complicated multilayered protein complex. "Understanding kinetochores is a
tremendous challenge, as they consist of several layers, each made
of many interacting building blocks" says Musacchio. "The outermost
layer, the corona, has retained some of the most interesting secrets
of the kinetochore. Its assembly is particularly interesting, since the
complex has a brief lifetime that ends right before the critical steps of chromosome alignment and segregation." In a series of previous studies, Musacchio's laboratory made fundamental inroads into the structure and
function of the different layers of kinetochores and how they connect chromosomes to microtubules. To gain this knowledge, the group adopted
a reductionist approach named biochemical reconstitution. They produced
the individual components of the protein networks outside the cell, in
a test tube. They then reassembled them piece by piece to form an almost complete kinetochore that they could study in isolation, in a controlled
and simplified environment that contrasts with the enormously complex,
buzzing interior of a cell.
Applying the same strategy, the skilled team of two postdocs, Tobias
Raisch and Giuseppe Ciossani, two PhD students, Ennio d'Amico and
Verena Cmentowski, and other co-workers has now been able to rebuild
the kinetochore corona. They showed that only two components are
sufficient for that: the ROD-Zwilch-ZW10 (RZZ) protein complex and the
protein Spindly, which plays an essential role in the interaction of the kinetochore with the microtubules. The corona assembles exclusively on kinetochores, and the mechanisms that limit its growth to these structures
had remained a crucial unresolved question. By reconstituting the process
in vitro, the scientists were able to identify an enzyme, the kinase MPS1,
as the essential catalyst of RZZ corona assembly at the kinetochore.
One step closer to the crown Electron microscopy (EM) has accompanied
the study of kinetochores since the 1960's, but it wasn't until recently,
that burgeoning methodological developments made this technique able to visualize the building blocks at the atomic scale. "In 2017, we generated
the first ever 3D structural model of the RZZ complex by cryo-EM,"
says Raunser. "However, at the 1 nm resolution of this initial model,
it was impossible to observe the finest molecular details responsible
for biological function." The new structural analysis improved
the resolution to the point that atomic details emerged, finally
explaining how interactions of RZZ components with themselves and with
Spindly promote corona assembly into a large polymer that surrounds the kinetochore. "Our work crowns a succession of previous studies on the kinetochore corona, now providing us with a framework to understand the critical moment of cell division when the attachment of chromosomes to microtubules becomes essentially irreversible" concludes Musacchio. The
team's future studies will try to integrate the corona into reconstituted kinetochores, moving a new important step towards the reconstitution of chromosome segregation in vitro, a goal of extraordinary ambition that
will shed light on the basis of a most fundamental process of life.
========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Physiology. Note: Content may be edited
for style and length.
========================================================================== Journal Reference:
1. Tobias Raisch, Giuseppe Ciossani, Ennio d'Amico, Verena Cmentowski,
Sara
Carmignani, Stefano Maffini, Felipe Merino, Sabine Wohlgemuth,
Ingrid R Vetter, Stefan Raunser, Andrea Musacchio. Structure
of the RZZ complex and molecular basis of Spindly‐driven
corona assembly at human kinetochores. The EMBO Journal, 2022;
DOI: 10.15252/embj.2021110411 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220408103122.htm
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